tbuckley/cabot-search huggingface dataset:
Precision cut intestinal slices, a novel model of acute food allergic reactions
Authors: Lisa Hung, Alper Celik, Xiaojun Yin, Kai Yu, Alireza Berenjy, Akash Kothari, Helena Obernolte, Julia E. M. Upton, Katrine Lindholm Bøgh, Gino R. Somers, Iram Siddiqui, Martin Grealish, Fayez A. Quereshy, Katherina Sewald, Priscilla P. L. Chiu, Thomas Eiwegger
Journal: Allergy (2022)

Food allergy affects up to 10% of the pediatric population. Despite ongoing efforts, treatment options remain limited. Novel models of food allergy are needed to study response patterns downstream of IgE-crosslinking and evaluate drugs modifying acute events. Here, we report a novel human ex vivo model that displays acute, allergen-specific, IgE-mediated smooth muscle contractions using precision cut intestinal slices (PCIS).PCIS were generated using gut tissue samples from children who underwent clinically indicated surgery. Viability and metabolic activity were assessed from 0 to 24 h. Distribution of relevant cell subsets was confirmed using single nucleus RNA sequencing. PCIS were passively sensitized using plasma from peanut allergic donors or peanut-sensitized non-allergic donors, and exposed to various stimuli including serotonin, histamine, FcɛRI-crosslinker, and food allergens. Smooth muscle contractions and mediator release functioned as readouts. A novel program designed to measure contractions was developed to quantify responses. The ability to demonstrate the impact of antihistamines and immunomodulation from peanut oral immunotherapy (OIT) was assessed.PCIS viability was maintained for 24 h. Cellular distribution confirmed the presence of key cell subsets including mast cells. The video analysis tool reliably quantified responses to different stimulatory conditions. Smooth muscle contractions were allergen-specific and reflected the clinical phenotype of the plasma donor. Tryptase measurement confirmed IgE-dependent mast cell-derived mediator release. Antihistamines suppressed histamine-induced contraction and plasma from successful peanut OIT suppressed peanut-specific PCIS contraction.PCIS represent a novel human tissue-based model to study acute, IgE-mediated food allergy and pharmaceutical impacts on allergic responses in the gut.
Nanofiber-coated, tacrolimus-eluting sutures inhibit post-operative neointimal hyperplasia in rats
Authors: Kunal S Parikh, Aditya Josyula, Takahiro Inoue, Takuma Fukunishi, Huaitao Zhang, Revaz Omiadze, Richard Shi, Youseph Yazdi, Justin Hanes, Laura M Ensign, Narutoshi Hibino
Journal: Journal of Controlled Release (2022)
Incomplete resection of colorectal polyps of 4–20 mm in size when using a cold snare, and its associated factors
Authors: Daniel von Renteln, Roupen Djinbachian, Florence Benard, Alan N. Barkun, Mickael Bouin, Simon Bouchard, Érik Deslandres, Benoit Panzini, Sacha Sidani, Raymond Leduc, Bruce C. Jobse, Heiko Pohl
Journal: Endoscopy (2022)

BACKGROUND : Cold snare polypectomy (CSP) is increasingly used for polypectomy and is recommended as the first-line modality for small (< 10 mm) polyps. This study aimed to evaluate incomplete resection rates (IRRs) when using CSP for colorectal polyps of 4-20 mm. METHODS : Adults (45-80 years) undergoing screening, surveillance, or diagnostic colonoscopy and CSP by one of nine endoscopists were included. The primary outcome was the IRR for colorectal polyps of 4-20 mm, defined as the presence of polyp tissue in marginal biopsies after resection of serrated polyps or adenomas. Secondary outcomes included the IRR for serrated polyps, ease of resection, and complications. RESULTS: 413 patients were included (mean age 63; 48 % women) and 182 polyps sized 4-20 mm were detected and removed by CSP. CSP required conversion to hot snare resection in < 1 % of polyps of < 10 mm and 44 % of polyps sized 10-20 mm. The IRRs for polyps < 10 mm and ≥ 10 mm were 18 % and 21 %. The IRR was higher for serrated polyps (26 %) compared with adenomas (16 %). The IRR was higher for flat (IIa) polyps (odds ratio [OR] 2.9, 95 %CI 1.1-7.4); and when resection was judged as difficult (OR 4.2, 95 %CI 1.5-12.1), piecemeal resection was performed (OR 6.6, 95 %CI 2.0-22.0), or visible residual polyp was present after the initial resection (OR 5.4, 95 %CI 2.0-14.9). Polyp location, use of a dedicated cold snare, and submucosal injection were not associated with incomplete resection. Intraprocedural bleeding requiring endoscopic intervention occurred in 4.7 %. CONCLUSIONS : CSP for polyps of 4-9 mm is safe and feasible; however, for lesions ≥ 10 mm, CSP failure occurs frequently, and the IRR remains high even after technical success. Incomplete resection was associated with flat polyps, visual residual polyp, piecemeal resection, and difficult polypectomies.
How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure
Authors: Milton Packer
Journal: European Journal of Heart Failure (2022)

Many patients with heart failure have an iron‐deficient state, which can limit erythropoiesis in erythroid precursors and ATP production in cardiomyocytes. Yet, treatment with sodium–glucose cotransporter 2 (SGLT2) inhibitors produces consistent increases in haemoglobin and haematocrit, even in patients who are iron‐deficient before treatment, and this effect remains unattenuated throughout treatment even though SGLT2 inhibitors further aggravate biomarkers of iron deficiency. Heart failure is often accompanied by systemic inflammation, which activates hepcidin, thus impairing the duodenal absorption of iron and the release of iron from macrophages and hepatocytes, leading to a decline in circulating iron. Inflammation and oxidative stress also promote the synthesis of ferritin and suppress ferritinophagy, thus impairing the release of intracellular iron stores and leading to the depletion of bioreactive cytosolic Fe 2+ . By alleviating inflammation and oxidative stress, SGLT2 inhibitors down‐regulate hepcidin, upregulate transferrin receptor protein 1 and reduce ferritin; the net result is to increase the levels of cytosolic Fe 2+ available to mitochondria, thus enabling the synthesis of heme (in erythroid precursors) and ATP (in cardiomyocytes). The finding that SGLT2 inhibitors can induce erythrocytosis without iron supplementation suggests that the abnormalities in iron diagnostic tests in patients with mild‐to‐moderate heart failure are likely to be functional, rather than absolute, that is, they are related to inflammation‐mediated trapping of iron by hepcidin and ferritin, which is reversed by treatment with SGLT2 inhibitors. An increase in bioreactive cytosolic Fe 2+ is also likely to augment mitochondrial production of ATP in cardiomyocytes, thus retarding the progression of heart failure. These effects on iron metabolism are consistent with (i) proteomics analyses of placebo‐controlled trials, which have shown that biomarkers of iron homeostasis represent the most consistent effect of SGLT2 inhibitors; and (ii) statistical mediation analyses, which have reported striking parallelism of the effect of SGLT2 inhibitors to promote erythrocytosis and reduce heart failure events.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

Breaking Insights| November 15 2022 Highlights from Recent Cancer Literature Author & Article Information Online ISSN: 1538-7445 Print ISSN: 0008-5472 ©2022 American Association for Cancer Research2022American Association for Cancer Research Cancer Res (2022) 82 (22): 4105–4106. https://doi.org/10.1158/0008-5472.CAN-82-22-BI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record November 15 2022 Citation Highlights from Recent Cancer Literature. Cancer Res 15 November 2022; 82 (22): 4105–4106. https://doi.org/10.1158/0008-5472.CAN-82-22-BI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Genomic deletion of tumor suppressor genes can also result in loss of nearby genes that force tumor cells to utilize compensatory pathways to sustain viability. This observation has led to interest in the concept of “collateral lethality,” which aims to therapeutically target these compensatory mechanisms to open more treatment strategies for patients. Achreja and colleagues developed the collateral lethal gene identification via metabolic flux (CLIM) approach to identify MTHFD2 as a collateral lethal gene in UQCR11-deleted ovarian tumors. They identified 19p13.3, containing the ubiquinol-cytochrome C reductase, complex III subunit XI (UQCR11) gene, as the most prevalent deletion in high-grade serous ovarian carcinoma. As UQCR11 encodes part of the electron transport chain (ETC), the authors hypothesized that ovarian cancers with 19p13.3 deletions have ETC impairments and rely on other metabolic pathways to maintain energy requirements. Using multi-objective metabolic flux analysis, they identified methylenetetrahydrofolate dehydrogenase (MTHFD2) as a... You do not currently have access to this content.
The Risk of Severe Hypoglycemia and Mortality in Patients With Type 2 Diabetes and Discharged With Acute Liver Injury
Authors: Fu-Shun Yen, Ming-Chih Hou, Chun-Wei Pan, Jia-Sin Liu, Chih-Cheng Hsu, Chii-Min Hwu
Journal: Diabetes Care (2022)

OBJECTIVE To compare the risks of severe hypoglycemia and mortality between patients with type 2 diabetes (T2D) and discharged with and without acute liver injury. RESEARCH DESIGN AND METHODS From 1 January 2000 to 31 December 2010, we identified patients with T2D and hospitalization for acute liver injury and hospitalization for other causes from the National Health Insurance Research Database of Taiwan. Multivariable-adjusted Cox proportional hazards models were used to compare the risks of severe hypoglycemia and mortality between the study and control groups. RESULTS The incidence rates and adjusted hazard ratios (aHRs) for severe hypoglycemia within 90 days and 365 days after discharge were 12.28 and 5.59/1,000 person-years (aHR 1.92 [1.30–2.85]) and 7.35 and 2.9/1,000 person-years (aHR 1.98 [1.52–2.58]) for patients discharged with and without acute liver injury, respectively. The incidence rates and aHRs for mortality within 90 days and 365 days after discharge were 82.4 and 27.54/1,000 person-years (aHR 1.73 [1.46–2.05]) and 36.8 and 9.3/1,000 person-years (aHR 1.94 [1.69–2.24]) for patients discharged with and without acute liver injury, respectively. The subgroup analysis of hypoglycemia risk in patients discharged with acute liver injury revealed no significant interaction in risk factors of age, chronic kidney disease, and medications, except for sex difference, which has significant interaction. CONCLUSIONS This cohort study demonstrated that patients with T2D and discharged with acute liver injury showed significantly higher risks of severe hypoglycemia and mortality within 90 days and 365 days after discharge than patients discharged with other causes.
Non-alcoholic fatty liver disease: the pathologist’s perspective
Authors: Wei-Qiang Leow, Anthony Wing-Hung Chan, Paulo Giovanni L. Mendoza, Regina Lo, Kihan Yap, Haeryoung Kim
Journal: Clinical and Molecular Hepatology (2022)

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of diseases characterized by fatty accumulation in hepatocytes, ranging from steatosis, non-alcoholic steatohepatitis, to cirrhosis. While histopathological evaluation of liver biopsies plays a central role in the diagnosis of NAFLD, limitations such as the problem of interobserver variability still exist and active research is underway to improve the diagnostic utility of liver biopsies. In this article, we provide a comprehensive overview of the histopathological features of NAFLD, the current grading and staging systems, and discuss the present and future roles of liver biopsies in the diagnosis and prognostication of NAFLD.
Effects of empagliflozin on erythropoiesis in heart failure: data from the Empire <scp>HF</scp> trial
Authors: Camilla Fuchs Andersen, Massar Omar, Andreas Glenthøj, Daniel El Fassi, Holger J. Møller, Jørgen A. Lindholm Kurtzhals, Bjarne Styrishave, Caroline Kistorp, Christian Tuxen, Mikael K. Poulsen, Jens Faber, Lars Køber, Finn Gustafsson, Jacob E. Møller, Morten Schou, Jesper Jensen
Journal: European Journal of Heart Failure (2022)

It remains unknown whether the consistently observed increase in haematocrit with sodium-glucose cotransporter 2 inhibitors is caused by diuresis-associated haemoconcentration or increased erythropoiesis. We aimed to investigate the early effect of empagliflozin on erythropoiesis and iron metabolism in patients with heart failure with reduced ejection fraction (HFrEF).The Empire HF was a double-blind, randomized, placebo-controlled trial. Patients with a left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) class I-III symptoms, and on stable guideline-directed HFrEF therapy were randomly assigned (1:1) to empagliflozin or matching placebo once daily for 12 weeks. Exploratory outcomes reflecting changes in erythropoiesis and iron metabolism were analysed. In total, 190 patients were randomized. Baseline characteristics were well-balanced between the groups (age: mean 64 [± 11] years; male: 85%; LVEF: mean 29 [± 8)%; NYHA class II: 78%; type 2 diabetes: 13%; anaemia: 28%; chronic kidney disease: 13%). In this post hoc analysis, erythropoietin was increased with empagliflozin compared to placebo from baseline to 12 weeks (adjusted mean difference 2.6 IU/L, 95% confidence interval [CI] 0.8-4.4; p = 0.0046). Moreover, hepcidin was reduced (adjusted ratio of change 0.76, 95% CI 0.59-0.97; p = 0.031), with no change observed for erythroferrone (adjusted ratio of change 1.17, 95% CI 0.86-1.60; p = 0.31) compared to placebo. No significant treatment-by-subgroup interactions were observed regarding baseline type 2 diabetes, anaemia, or chronic kidney disease (pinteraction >0.05).These findings suggest that empagliflozin increases erythropoiesis and augments early iron utilization in patients with HFrEF. These mechanisms may contribute to the cardioprotective properties of empagliflozin.
JHEP at a glance (December 2022)
Authors: Beom Kim, Nobuharu Tamaki, Claude Sirlin, Atsushi Nakajima, Rohit Loomba, Cheng Tian, Xuewen Min, Yongxu Zhao, Yu Li, Ben Zhou, Qiurong Ding, Kalliopi Pafili, Sabine Kahl, Lucia Mastrototaro, Irene Esposito, Matthias Schlensak, Michael Roden, Julien Calderaro, Di Luca, Pascale Tommaso, Valérie Maillé, Jeanne Paradis, Stefano Shen, Nofar Rosenberg, Matthias Van Haele, Tali Lanton, Tania Roskams, Mathias Heikenwalder, Eithan Galun
Journal: Journal of Hepatology (2022)
Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer
Authors: Yin-Hao Shi, Qiong-Cong Xu, Ying-Qin Zhu, Zhi-De Liu, Guang-Yin Zhao, Qi Liu, Xi-Yu Wang, Jie-Qin Wang, Xiang Xu, Qiao Su, Jia-Ming Lai, Chen-Song Huang, Xiao-Yu Yin
Journal: Molecular Therapy (2022)

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.
Aetiology and diagnostics of paediatric hydrocephalus across Africa: a systematic review and meta-analysis
Authors: Camilla G Aukrust, Anne Henriette Paulsen, Enoch Ogbonnaya Uche, Patrick Dongosolo Kamalo, Irene Sandven, Heidi E Fjeld, Hilde Strømme, Per Kristian Eide
Journal: The Lancet Global Health (2022)

BackgroundWe aimed to identify the aetiological distribution and the diagnostic methods for paediatric hydrocephalus across Africa, for which there is currently scarce evidence.MethodsIn this systematic review and meta-analysis, we searched MEDLINE (Ovid), the Cochrane Database of Systematic Reviews (Wiley), Embase (Ovid), Global Health (Ovid), Maternity & Infant Care (Ovid), Scopus, African Index Medicus (Global Index Medicus, WHO) and Africa-Wide Information (EBSCO) from inception to Nov 29, 2021. We included studies from any African country reporting on the distribution of hydrocephalus aetiology in children aged 18 years and younger, with no language restrictions. Hydrocephalus was defined as radiological evidence of ventriculomegaly or associated clinical symptoms and signs of the disorder, or surgical treatment for hydrocephalus. Exclusion criteria were studies only reporting on one specific subgroup or one specific cause of hydrocephalus. We also excluded conference and meetings abstracts, grey literature, editorials, commentaries, historical reviews, systematic reviews, case reports and clinical guidelines, as well as studies on non-humans, fetuses, or post-mortem reports. The proportions of postinfectious hydrocephalus, non-postinfectious hydrocephalus, and hydrocephalus related to spinal dysraphism were calculated using a random-effects model. Additionally, we included a category for unclear cases. Diagnostic methods were described qualitatively. To assess methodological study quality, we applied critical appraisal checklists provided by the Joanna Briggs Institute. The study was registered in Prospero (CRD42020219038).FindingsOur search yielded 3783 results, of which 1880 (49·7%) were duplicates and were removed. The remaining 1903 abstracts were screened and 122 (6·4%) full articles were sought for retrieval; of these, we included 38 studies from 18 African countries that studied a total of 6565 children. The pooled proportion of postinfectious hydrocephalus was 28% (95% CI 22–36), non-postinfectious hydrocephalus was 21% (95% CI 13–30), and of spinal dysraphism was 16% (95% CI 12–20), with substantial heterogeneity. The pooled proportion of hydrocephalus of unclear aetiology was 20% (95% CI 13–28).InterpretationOur findings suggest that postinfectious hydrocephalus is the single most common cause of paediatric hydrocephalus in Africa. For targeted investments to be optimal, there is a need for consensus regarding the aetiological classification of hydrocephalus and improved access to diagnostic services.FundingRikshospitalet, Oslo University Hospital, Oslo, Norway.
Global impact of COVID-19 on childhood tuberculosis: an analysis of notification data
Authors: Lasith Ranasinghe, Jay Achar, Matthias I Gröschel, Elizabeth Whittaker, Peter J Dodd, James A Seddon
Journal: The Lancet Global Health (2022)

There is concern that the COVID-19 pandemic has damaged global childhood tuberculosis management. Quantifying changes in childhood tuberculosis notifications could support more targeted interventions to restore childhood tuberculosis services. We aimed to use time-series modelling to evaluate the impact of COVID-19 on child tuberculosis notifications.Annual tuberculosis case notification data reported to WHO by 215 countries were used to calculate annual notification counts for the years 2014-20, stratified by age groups (0-4, 5-14, and ≥15 years) and sex. We used time-series modelling to predict notification counts for 2020, and calculated differences between these predictions and observed notifications in 2020 for each of the six WHO regions and at the country level for 30 countries with high tuberculosis burden. We assessed associations between these differences and the COVID-19 stringency index, a measure of COVID-19 social impact.From 2014 to 2019, annual tuberculosis notification counts increased across all age groups and WHO regions. More males than females in the 0-4 years age group and ≥15 years age group had notifications in all years from 2014 to 2020 and in all WHO regions. In the 5-14 years age group, more females than males were notified globally in all years, although some WHO regions had higher notifications from males than females. In 2020, global notifications were 35·4% lower than predicted (95% prediction interval -30·3 to -39·9; 142 525 observed vs 220 794 predicted notifications [95% prediction interval 204 509 to 237 078]) for children aged 0-4 years, 27·7% lower (-23·4 to -31·5; 256 398 vs 354 578 [334 724 to 374 431]) in children aged 5-14 years, and 18·8% lower (-15·4 to -21·9; 5 391 753 vs 6 639 547 [6 375 086 to 6 904 007]) for people aged 15 years or older. Among those aged 5-14 years, the reduction in observed relative to predicted notifications for 2020 was greater in males (-30·9% [-24·8 to -36·1]) than females (-24·5% [-18·1 to -29·9]). Among 28 countries with high tuberculosis burden, no association was observed between the stringency of COVID-19 restrictions and the relative difference in observed versus predicted notifications.Our findings suggest that COVID-19 has substantially affected childhood tuberculosis services, with the youngest children most affected. Although children have mostly had fewer severe health consequences from COVID-19 than have adults, they have been disproportionately affected by the effects of the pandemic on tuberculosis care. Observed sex differences suggest that targeted interventions might be required. As countries rebuild health systems following the COVID-19 pandemic, it is crucial that childhood tuberculosis services are placed centrally within national strategic plans.Medical Research Council.
Low-level viraemia among people living with HIV in Nigeria: a retrospective longitudinal cohort study
Authors: Helen M Chun, Andrew Abutu, Kyle Milligan, Akipu Ehoche, Ray W Shiraishi, Solomon Odafe, Ibrahim Dalhatu, Dennis Onotu, McPaul Okoye, Ademola Oladipo, Jerry Gwamna, Akudo Ikpeazu, Nseobong M Akpan, Jahun Ibrahim, Gambo Aliyu, Sulaiman Akanmu, Mary A Boyd, Mahesh Swaminathan, Tedd Ellerbrock, Kristen A Stafford, Emilio Dirlikov
Journal: The Lancet Global Health (2022)
Assessment of serological responses following vaccination campaigns with type 2 novel oral polio vaccine: a population-based study in Tajikistan in 2021
Authors: Azamdzhon Mirzoev, Grace R Macklin, Yiting Zhang, Bernardo A Mainou, Umeda Sadykova, Victor Stefan Olsavszky, Shahin Huseynov, Murodali Ruziev, Faizali Saidzoda, Mahtob Bobokhonova, Ondrej Mach
Journal: The Lancet Global Health (2022)
Valemetostat Tosilate: First Approval
Authors: Susan J. Keam
Journal: Drugs (2022)

Valemetostat tosilate (valemetostat; EZHARMIA®), a selective dual inhibitor of histone-lysine N-methyltransferases enhancer of zeste homolog 1 and 2 (EZH1/2), is being developed by Daiichi Sankyo Company, Ltd for the treatment of various haematological malignancies and solid tumours, including types of non-Hodgkin lymphomas (NHL). Valemetostat was approved in Japan in September 2022 for the treatment of patients with relapsed or refractory adult T-cell leukaemia/lymphoma (R/R ATL), a subtype of NHL. This article summarizes the milestones in the development of valemetostat leading to this first approval for R/R ATL.